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Animal models

Decreased cell stiffness enhances leukemia development and progression

Leukemia volume 34, pages 2493–2497 (2020)Cite this article

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Emerging evidence has linked cell mechanics to functional behaviors [1]. The biophysical traits of a single cell are inextricably linked to the cytoskeleton. It has become increasingly evident that intrinsic and extrinsic mechanical properties, which describe the resistance to deformation (elasticity) or flow (viscosity) in response to an applied force, regulate cellular activities, such as cell morphology, adhesion, migration, and trafficking. Recent studies have demonstrated that solid tumor cells with higher migratory and invasive potential are softer than cells with lower migration and invasion potential [2,3,4,5]. However, how cell intrinsic mechanical properties might affect liquid tumor (leukemia) development and progression remains unclear.

Protein tyrosine phosphatase, non-receptor type 21 (Ptpn21), a poorly studied tyrosine phosphatase [6], binds to actin filaments and regulates cytoskeleton-associated cellular processes [7]. We have recently shown that Ptpn21 plays an important role in maintaining cell mechanical properties [8], and that it helps retain hematopoietic stem cells (HSCs) in the bone marrow (BM) niche through a biomechanical mechanism [8]. Knockout of Ptpn21 results in impaired retention of HSCs within BM niches. Ptpn21 knockout stem cells exhibit enhanced mobility and spontaneous egress into the peripheral blood. These phenotypes were attributable to the decrease in cellular mechanical stiffness and the increase in cell deformability [8]. Mechanistically, Ptpn21 functions by dephosphorylating Spetin1 (Tyr246) [8], a rarely described component of the cytoskeleton. Importantly, missense mutations and frameshift truncating mutations in PTPN21 have been identified in chronic lymphocytic leukemia (IntOGen—mutational cancer drivers database) and colon cancer [9,10,11], respectively. However, the pathogenic effects of PTPN21 loss-of-function mutations remain to be determined.

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Fig. 1: Deletion of Ptpn21 promotes development and progression of MLL-AF9-induced leukemia.
Fig. 2: Cellular mechanical properties but not cell signaling activities are impacted in Ptpn21-deleted MLL leukemic cells that proliferate faster than control cells in vivo.

References

  1. Fletcher DA, Mullins RD. Cell mechanics and the cytoskeleton. Nature. 2010;463:485–92.

    Article  CAS  Google Scholar 

  2. Tse HT, Gossett DR, Moon YS, Masaeli M, Sohsman M, Ying Y, et al. Quantitative diagnosis of malignant pleural effusions by single-cell mechanophenotyping. Sci Transl Med. 2013;5:212ra163.

    Article  Google Scholar 

  3. Byun S, Son S, Amodei D, Cermak N, Shaw J, Kang JH, et al. Characterizing deformability and surface friction of cancer cells. Proc Natl Acad Sci USA. 2013;110:7580–5.

    Article  CAS  Google Scholar 

  4. Cross SE, Jin YS, Rao J, Gimzewski JK. Nanomechanical analysis of cells from cancer patients. Nat Nanotechnol. 2007;2:780–3.

    Article  CAS  Google Scholar 

  5. Plodinec M, Loparic M, Monnier CA, Obermann EC, Zanetti-Dallenbach R, Oertle P, et al. The nanomechanical signature of breast cancer. Nat Nanotechnol. 2012;7:757–65.

    Article  CAS  Google Scholar 

  6. Moller NP, Moller KB, Lammers R, Kharitonenkov A, Sures I, Ullrich A. Src kinase associates with a member of a distinct subfamily of protein-tyrosine phosphatases containing an ezrin-like domain. Proc Natl Acad Sci USA. 1994;91:7477–81.

    Article  CAS  Google Scholar 

  7. Carlucci A, Gedressi C, Lignitto L, Nezi L, Villa-Moruzzi E, Avvedimento EV, et al. Protein-tyrosine phosphatase PTPD1 regulates focal adhesion kinase autophosphorylation and cell migration. J Biol Chem. 2008;283:10919–29.

    Article  CAS  Google Scholar 

  8. Ni F, Yu WM, Wang X, Fay ME, Young KM, Qiu Y, et al. Ptpn21 controls hematopoietic stem cell homeostasis and biomechanics. Cell Stem Cell. 2019;24:608–20.

    Article  CAS  Google Scholar 

  9. Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K, et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet. 2014;46:1264–6.

    Article  CAS  Google Scholar 

  10. Korff S, Woerner SM, Yuan YP, Bork P, von Knebel Doeberitz M, Gebert J. Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability. BMC Cancer. 2008;8:329.

    Article  Google Scholar 

  11. Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660–4.

    Article  CAS  Google Scholar 

  12. Cardone L, Carlucci A, Affaitati A, Livigni A, DeCristofaro T, Garbi C, et al. Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. Mol Cell Biol. 2004;24:4613–26.

    Article  CAS  Google Scholar 

  13. Carlucci A, Porpora M, Garbi C, Galgani M, Santoriello M, Mascolo M, et al. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J Biol Chem. 2010;285:39260–70.

    Article  CAS  Google Scholar 

  14. Rosenbluth MJ, Lam WA, Fletcher DA. Analyzing cell mechanics in hematologic diseases with microfluidic biophysical flow cytometry. Lab Chip. 2008;8:1062–70.

    Article  CAS  Google Scholar 

  15. Fay ME, Myers DR, Kumar A, Turbyfield CT, Byler R, Crawford K, et al. Cellular softening mediates leukocyte demargination and trafficking, thereby increasing clinical blood counts. Proc Natl Acad Sci USA. 2016;113:1987–92.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health grants HL130995 and DK092722, and a St. Baldrick’s Foundation reseach grant (to C-KQ).

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  1. These authors contributed equally: Linping Hu, Fang Ni

Authors and Affiliations

  1. Department of Pediatrics, Division of Hematology and Oncology, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, 30322, USA

    Linping Hu, Fang Ni, Xinyi Wang, Meredith E. Fay, Wilbur A. Lam & Cheng-Kui Qu

  2. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    Meredith E. Fay, Katherine M. Young, Wilbur A. Lam & Todd A. Sulchek

  3. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    Todd A. Sulchek

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  1. Linping Hu
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Contributions

LH, FN, and XW conducted mouse experiments and summarized the data. MEF performed microfluidics assays. KMY performed the Atomic Force Microscope measurements. WAL and TAS provided critical advice. C-KQ designed the experiments and directed the entire project. LH, FN, and C-KQ wrote the manuscript.

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Correspondence to Cheng-Kui Qu.

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Hu, L., Ni, F., Wang, X. et al. Decreased cell stiffness enhances leukemia development and progression. Leukemia 34, 2493–2497 (2020). https://doi.org/10.1038/s41375-020-0763-7

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